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Introduction: In Malawi, HIV-infected pregnant and breastfeeding women are offered lifelong antiretroviral therapy (ART) regardless of CD4 count or clinical stage (Option B+). Their HIV-exposed children are enrolled in the national prevention of mother-to-child transmission (PMTCT) programme, but many are lost to follow-up. We estimated the cumulative incidence of vertical HIV transmission, taking loss to follow-up into account. Methods: We abstracted data from HIV-exposed children enrolled into care between September 2011 and June 2014 from patient records at 21 health facilities in central and southern Malawi. We used competing risk models to estimate the probability of loss to follow-up, death, ART initiation and discharge, and used pooled logistic regression and inverse probability of censoring weighting to estimate the vertical HIV transmission risk. Results: A total of 11,285 children were included; 9285 (82%) were born to women who initiated ART during pregnancy. At age 30 months, an estimated 57.9% (95% CI 56.6-59.2) of children were lost to follow-up, 0.8% (0.6-1.0) had died, 2.6% (2.3-3.0) initiated ART, 36.5% (35.2-37.9) were discharged HIV-negative and 2.2% (1.5-2.8) continued follow-up. We estimated that 5.3% (95% CI 4.7-5.9) of the children who enrolled were HIV-infected by the age of 30 months, but only about half of these children (2.6%; 95% CI 2.3-2.9) were diagnosed. Conclusions: Confirmed mother-to-child transmission rates were low, but due to poor retention only about half of HIV-infected children were diagnosed. Tracing of children lost to follow-up and HIV testing in outpatient clinics should be scaled up to ensure that all HIV-positive children have access to early ART.
In Malawi, HIV-positive pregnant and breastfeeding women are offered lifelong ART according to WHO’s Option B+ policy. HIV-exposed children are enrolled in the national PMTCT programme as soon after birth as possible. Clinic follow-up of children begins at 6 weeks of age. During the first 6 months, children are seen monthly, thereafter every 3 months. Children receive nevirapine prophylaxis for 6 weeks and cotrimoxazole prophylaxis until their final negative HIV status has been confirmed. They are HIV tested with a HIV-1 DNA polymerase chain reaction test at 6 weeks of age, and again with rapid antibody testing when they are 12 and 24 months old. Children are again tested 6 weeks after weaning of breastfeeding to confirm the final negative HIV status before they are discharged. Children diagnosed with HIV are referred for ART initiation [13]. We included HIV-exposed children who enrolled in Malawi’s national PMTCT programme between 1 September 2011 and 30 June 2014 at one of the 21 large health facilities including health centres, district hospitals, faith-based hospitals and central hospitals from a diverse geographical area in the central and southern region of Malawi who participated in our previous studies of the implementation of Option B+ in Malawi [7–9]. We selected these facilities because they were using the Baobab Health Antiretroviral Therapy (BART) electronic medical record system in September 2011, when the Option B+ programme was launched. Health facilities were classified by the Ministry of Health. Health centres are primary-care facilities, district and faith-based hospitals are secondary-care facilities and central hospitals are tertiary-care facilities. Faith-based hospitals are operated by faith-based organizations. We followed the children up to 26 June 2015. We excluded children whose birthdate was missing, and children born to mothers who received antepartum antiretroviral (ARVs) medication that were no longer recommended in the Malawi’s Integrated HIV Management guidelines (Figure 1) [13]. Flow chart of eligibility of study participants. Registration and follow-up data for HIV-exposed children enrolled in the HIV care programme are routinely collected on standardized paper-based forms kept at the health facilities. Paper-based records were manually captured into an electronic database. To reduce data entry errors, data entry clerks entered the records twice, independently. Inconsistencies were resolved by a third reviewer. Registers were de-duplicated using probabilistic record linkage methods. More details on data collection are given in the appendix (Text S1). We analysed the risk of mother-to-child transmission and PMTCT programme outcomes. The endpoints for mother-to-child transmission were the unweighted (observed) cumulative incidence of HIV infection, and the weighted cumulative incidence of HIV infection defined as the sum of the observed cumulative incidence of HIV infection plus the unobserved cumulative incidence of HIV infection in children who were lost to follow-up or not tested for HIV (i.e., the risk of HIV infection that we would have observed if all enrolled children were retained and tested according to the guidelines, after 6 weeks, 12 months and 24 months) [13]. Children were classified as HIV-infected if they tested positive with HIV-1 DNA testing at any time during follow-up, or if their HIV rapid antibody test was positive when they were 12 months or older, or if they were presumptively diagnosed, based on clinical conditions that constitute presumed severe HIV disease and a positive HIV rapid test before they were 12 months old and no later negative test [13]. The endpoints for PMTCT programme outcomes were the estimated proportions of children not yet enrolled into care, retained in care, lost to follow-up, discharged confirmed HIV-free, initiated ART and the proportion of children who died. Children who missed a clinic appointment for more than 60 days and did not return to care thereafter were classified as lost to follow-up. Children who had received a negative HIV test result at least 6 weeks after the end of breastfeeding were discharged confirmed HIV-free. Children were classified as retained in care if they had enrolled into care, and had not been discharged confirmed HIV-free, were not lost to follow-up, had not transferred out, had not initiated ART and had not died. We estimated unweighted and weighted Kaplan–Meier failure functions for children’s cumulative incidence of HIV infection in pooled logistic regression. We used inverse probability of censoring weighting to account for HIV infections that would have been observed if all children who enrolled were retained in care and tested according to the guidelines [19,20]. In the weighted analysis, children who were not tested were represented by children who had similar characteristics and were tested. Characteristics considered included infant nevirapine prophylaxis at birth (no, yes, unknown), infant nevirapine prophylaxis after birth (no, yes, unknown), ARVs given to mother during pregnancy (none, mother on triple ART for <4 weeks, mother on triple ART ≥4 weeks, unknown), ARVs given to mother in labour (none, single dose nevirapine, mother on triple ART, unknown), type of facility (faith-based hospital, health centre, district hospital, central hospital), time-updated maternal ART coverage during breastfeeding (on ART, not on ART) and maternal death (yes, no). We calculated approximate 95% confidence intervals (CIs) for the cumulative incidence of HIV infection, using an error factor [21]. We multiplied cumulative incidences by 100 to express cumulative risk of HIV infection as the percentage of HIV-infected children. Text S2 provides more details on the statistical methods we used to estimate the risk of mother-to-child transmission. The analysis was done in STATA (version 14) and data were plotted in R (version 3.2.2). We developed a multi-state model within a competing risk framework to estimate the proportions of children who experienced six PMTCT programme outcomes: enrolment into care, retention in care, loss to follow-up, ART initiation, discharge and death). We fitted the model in the R package mstate [22,23]. The structure of the model is shown in Figure 2. From birth to enrolment into care, children were in State 1 (“not yet enrolled”). On the day they enrolled into the PMTCT programme, children switched to State 2 (“retained in care”), where they remained until they were either discharged confirmed HIV-free (State 3), lost to follow-up (State 4), initiated ART (State 5) or died (State 6). We followed children until the day of discharge, loss to follow-up, death or ART initiation for a maximum follow-up time of 30 months. Children were censored if their follow-up ended, or if they were transferred out. The appendix contains a technical description of the model (Text S2). We compared PMTCT programme outcomes between children at low risk (children who received nevirapine prophylaxis at and after birth and were born to mothers who received at least 4 weeks of triple ART) and high risk (children who received no nevirapine prophylaxis and were born to mothers who received no triple ART) of mother-to-child transmission. We predicted and plotted the percentage of children who had experienced a PMTCT programme outcome separately for children with the low- and high-risk profile. The adjusted hazard ratios (aHRs) from the model we used for the predictions are shown in Table S1. Multi-state model. The boxes represent the six states of the multi-state model and the black triangles represent the events that trigger transitions between states. All children start in State 1 “not yet enrolled” when they are born, and switch to State 2 “retained in care” after they enrolled into HIV care. Children remain in State 2 until they were discharged HIV-negative (State 3), lost to follow-up (State 4), initiated ART (State 5) or died (State 6), or else, until their follow-up ended. States 3 to 6 are absorbing states (i.e. children who have entered an absorbing state remain in this state). We fitted a multivariable Cox proportional hazards models in the framework of the multistate model to estimate unadjusted and aHRs for predictors of PMTCT programme outcomes. We considered the following predictors in multivariable analysis: gender (male, female, unknown); age at enrolment (in months); birthweight (≥2500g, <2500g, unknown); nevirapine prophylaxis at birth; nevirapine prophylaxis after birth; antepartum ARV exposure; intrapartum ARV exposure; and, facility type. The National Health Sciences Research Committee, Malawi and the Cantonal Ethics Committee of Bern, Switzerland granted ethical approval for the study and waived the requirement to obtain informed consent.
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